The overall objective of this ongoing work is the elucidation of mechanisms involved in the expression and dissemination of genes that encode antibiotic resistance in bacteria, and the modification of these processes as a result of information obtained. This proposed investigation has the following specific aims: (1) Study of genetic control mechanisms that regulate gene expression, and particularly, expression of plasmid-borne antibiotic resistance genes. (2) Study of the role of gene amplification in controlling the level of expression of certain kinds of bacterial antibiotic resistance. (3) Elucidation of the mechanism by which specific sequences on plasmid DNA interact with chromosomally encoded gene products to accomplish stable inheritance of antibiotic resistance plasmids in exponentially growing cell populations. (4) Isolation of antibiotic synthetic pathway genes from antibiotic-producing Streptomyces and the manipulation of these genes to yield biologically modified antibiotics that have reduced susceptibility to inactivation by antibiotic resistance plasmids. The proposed research is a multi-faceted five-year study based on the rationale than an understanding of fundamental genetic mechanisms operating in bacterial antibiotic resistance is of fundamental importance in the eventual control of such resistance in cell populations.